MSK L16 Pharmacology MSK Flashcards
Drugs used: in RA
NSAIDS
DMARDS
DMARDS role
- Aim to halt or slow the inflammatory joint destruction
- Slow onset of actions
- May have little long-term effect on disease
Molecular Mechanisms in RA: Highly complex multi-factor mediation of the pathological process
- Auto-immune response – auto-antibodies and immune complex
- T-cell mediated antigen-specific responses
- T-cell independent cytokine networks
Molecular Mechanisms in RA: What is certain
- T cells are a/the major driving force
- Nuclear factor (NF) –kB is activated in the synovium and regulates genes involved in inflammation e.g. TNF, IL etc iNOS and COX-2
- MAP kinases are activated in rheumatoid tissues – key regulator of cytokine and metalloproteinase production
NSAIDS
role
Symptomatic treatment – block eicosanoid synthese
→ Provides symptomatic relief of pain and stiffness, but do not alter disease progression.
DMARDS role
- To prevent erosive damage
- If patient intolerance to NSADS
- Extra-articular manifestations of RA
- Poor response to NSAIDS
DMARDS MOA
Sulphasalazine
Gold (aurothiomalalte and auranofin)
Methotrexate
DMARDS example
B and T cell action blocking bt unclear
Sulphasalazine: Epi
Cheap and commonly first choice in UK
Sulphasalazine: Combination of
Sulphapyridine combind with salicycate
Sulphasalazine: Hydrolysed by and to
By gut bacteria to sulphapyrieine and 5-aminosalicylic acid
Sulphasalazine: Suphapyridine action
Reduces absorption of antigens from colon that may promote joint inflammation
Sulphasalazine: 5-aminosalicyclic acid action
Reduces synthesis of inflammatory mediators e.g. eicosanoids and cytokines
Sulphasalazine: Side effects
- GI
- Reversible decrease in sperm count
- Sulphonamide idiosyncratic blood dyscrasias (reducetion in WBC and platelet)
- Analyphylaxis
Gold (aurothiomalate and Auranofin: Possible MOA
- Inhibit lymphocyte proliferation
- Inhibit release and activity of Lysosomal enzymes
- Decrease production of toxic O2 metabolites from phagocytes
- Inhibit chemotaxis of neutrophils
- Inhibit induction of IL-1 and TNF-alpha
Gold (aurothiomalate and Auranofin: Acts where
Binds to tissue proteins and accumulates widely, incuding in synovium of inflamed joints
Gold (aurothiomalate and Auranofin: Toxicity
Can be serious: 1. blood disorders – agranulocytosis, aplastic anaemia 2. Skin rashes 3. Diarrhoea 4. Glomerulonephritis Serious toxic effects in 10% of patiens
Methotrexate: Action speed
Rapid
Methotrexate: Use in
DMARD for RA and Chrohns
Methotrexate: MOA
Not via inhibition of dihydrofolatereductase (DHFR) – for DMARD unsure
Methotrexate: MOA thoughts
Thought to be via inhibition of enzymes involved in purine metabolism:
- Accumulation of adenosine
- Inhibition of T cell activation
- Suppression of adhesion molecule expression by by T-cell
Methotrexate
Time to Benefit
Potential for Toxicity
Toxcities to Monitor
1-2 months Moderate Myelosuppression Hepatic fibrosis and cirrhosis Pulmonary infiltrates
Hydroxychloquine
Time to Benefit
Potential for Toxicity
Toxcities to Monitor
2-6 months
Low
Macular Damage
Leflunomide
Time to Benefit
Potential for Toxicity
Toxcities to Monitor
4-12 wks Low Diarrhea Alopecia Rash Headache Risk of immunosuppression infection
Sulfasalazine
Time to Benefit
Potential for Toxicity
Toxcities to Monitor
1-3 months
Low
Myelosuppresion
Cyclosporin
Time to Benefit
Potential for Toxicity
Toxcities to Monitor
4-8 wks High Renal insufficiency Anaemia Hypertension
Gold, oral
Time to Benefit
Potential for Toxicity
Toxcities to Monitor
4-6 months
Low
Myelosupression
Proteinuria
Gold, parentral
Time to Benefit
Potential for Toxicity
Toxcities to Monitor
3-6 months
Moderate
Myelosupression
Proteinuria
Azathioprine
Time to Benefit
Potential for Toxicity
Toxcities to Monitor
2-3 months Moderate Myelosupression Hepatotoxicity Lymphoproliferative disorders
Minocycline
Time to Benefit
Potential for Toxicity
Toxcities to Monitor
1-3 months Low Hyperpigmentation Dizzines Vaginal yeast infections
Corticosteroids and RA: Uses
- Intra-articular injections of individual joints (e.g. knee)
- In active disease short causes of oral prednisolone, can produce a rapid onset before other drugs
Corticosteroids and RA: Standard therapy
Combination of low-dose glucocorticoids and sulphasalazine/methotrexate
Corticosteroids and RA:Mechanisms
- Immunosuppressants (act on cell-mediated immune responses)
* Decrease transcription of IL-2, TNF-alpha, interferon-y
Gout →Acute arthritis
Due to deposition of urate crystals in the synovial tissue – very painful
Gout →Metabolic disorder
Plasma urate concentration increased due to overproduction of purines and/or impaired excretion of purines
→ Seen with poor renal degradation
→ High red meat diet
→ Mostly genetic
Gout →Pathology
- Crystal deposition leads to kinin release/generation of LTB4
- Phagocytic neutrophil accumulation
- Free radical formation
- Call damage and lysis
Gout → Treatment
Inhibit uric acid synthesis
Increase uric acid secretion (uricosuric drugs)
Inhibit inflammatory cell migration into joints
Give anti-inflammation/analgesic drugs (NSAIDs)
Gout →Drugs for Gout
Allopurinol → blocks formation of uric acid
Colchicine → inhibits leckocyte migration into joints
Acute → NSAIDS not Aspirin
